A search using the key word “immunotherapy” on clinicaltrials.gov (1) results in >1900 hits for many different types of cancer indications and other illnesses e.g. autoimmune disease. This includes every thinkable therapy that involves the immune system – from vaccination to immune checkpoint inhibitors (e.g. anti PD1, PD-L1, CTLA4 antibodies) to immune-stimulator and many different types of agonists and antagonists targeting surface proteins that can be found on immune cells or that immune cells interact with e.g. so called CD+number proteins (cluster of differentiation: CD3, CD19, CD20, CD22, CD27, CD30, CD33, CD40, 137, ….).
A search of “immunotherapy and combination” decreases the number to almost 600 trials. This includes combinations of two different types of immunotherapies, IO + IO, or IO + chemotherapy, or IO + targeted therapy (e.g. a BRAF inhibitor in melanoma), or IO + radiation. Out of these ≈600 studies, 70 studies are phase III – again in different indications like different types of leukemia, lymphoma, melanoma, lung cancer, breast cancer, pancreatic, prostate , …… and others.
Some studies have not started yet, others are ongoing and enrolling patients or already met the enrollment target and might present data soon. Some of the studies were terminated showing it is challenging to find the right design, dose, schedule, endpoint, patient group or combination of drugs. Or safety can be a concern as well. Safety will be discussed in the fourth and last blog post of the IO series.
The high number of clinical studies sponsored by industry and academic institutions shows the great interest and the need for innovative therapies for cancer patients. The different trial designs show the need to find the best protocols to use IO. There are so many questions that have not been answered yet. What are the patients that benefit most from immunotherapy? How to select them? What are the best biomarkers? What is the right dosing? What is the best schedule? How many cycles of immunotherapy should be given to an individual patient – one cycle? … Six? And last but not least who is the right candidate for mono-therapy and what patient should undergo combination of therapies?
The body of literature about combining IO with other therapies is already vast. Hypotheses why IO combinations are beneficial include (3-5):
- Some targeted therapies e.g. HER2 therapy using trastuzumab in breast cancer depend on the immune system. Adding an immunotherapeutic to it is therefore suggestive of a synergistic effect.
- Cells of the immune system communicate with each other, which justifies the trial to target the immune system from different angles to support immune-surveillance of cancer cells.
- Certain therapies like radiation induce the expression of checkpoint proteins on the surface of cancer cells including PD1 and PD-L1. Several antibodies against these checkpoint proteins have been approved in the recent past and are currently tested in many different types of combinations listed on clinicaltrials.gov.
- Lymphocytic infiltration or inflammation of tumor tissue is a requirement for effective therapy and seen as a positive prognostic factor. In some patients PD-L1 expression and T-cell infiltration correlates but in many other patients it does not. In these patients anti PD1 or anti PD-L1 therapy alone would most likely not be effective. Therefore, a combination with a modulator that stimulates T cell recruitment may be necessary.
While the research community recognizes that the immune system is a major hallmark for anti-cancer therapy, there is still a lot to learn. IO research will most certainly remain an important focus for many more years if not decades. On the positive side, hundreds of patients have already significantly benefitted from this research and the findings and approvals coming out of it along the way.
- Combinations that work by Sarah Seton-Rogers (2012) Nature Reviews Cancer: Volume 12.
- Wu, CT, Chen, WC, Chang, YH, Lin WY and Chen MF (2016) The role of PD-L1 in the radiation response and clinical outcome for bladder cancer. Scientific Reports 6: 19740.
- Ritprajak, P. and Azuma, M. (2015) Intrinsic and extrinsic control of expression of the immunoregulatory molecular PD-L1 in epithelial cells and squamous cell carcinoma. Oral Oncology Volume 51: 221-228.